Acute Leukemias - Republican Scientific Medical Library

a 6.3 · Structural Aberrations 99
6.3.7 Translocations Involving Band (14q32)
Other than t(8;14)(q24;q32)
Abnormalities of the distal part of the long arm of chromosome
14 have been described in approximately 5% of
adult ALL patients [8]. The genes involved in t(14q32)
are the immunoglobulin heavy chain locus [72] and
the krüeppel zinc-finger gene (BCL11A) [73] on chromosome
14q32.3, both in B-lineage ALL, the TCL1 (T-cell
leukemia) gene on chromosome 14q32.1 [74] and the
distal region of a krüeppel-like zinc-finger transcription
factor BCL11B (also called CTIP2) on chromosome
14q32.2 [75, 76], both in T-lineage ALL. Many partner
chromosomes involved in translocations affecting
14q32 have been identified. In B-lineage ALL, the loci rearranged
with 14q32 include 1q21, 1q25, 2p13, 5q31, 8q11,
11q23, 18q21 and 19q13.1, and in T-lineage ALL, 5q35, and
14q11 [48].
6.3.8 del(6q)
Deletions of the long arm of chromosome 6 were reported
in 2–6% of adult ALL patients [1, 4–7, 77]. In
one large series, most deletions encompassed band
6q21 (in 20 of 23 patients), with del(6)(q12q16) being
present in three remaining patients [4]. In most patients,
del(6q) is found together with additional chromosome
abnormalities [8]. It is unclear, from data presented,
whether del(6q) represents a primary or secondary
cytogenetic abnormality. The outcome of patients
with del(6q) was somewhat better than that of patients
with a normal karyotype [4]. The genes involved in this
aberration are not identified to date. It seems clear that
MYB is not involved [78] but there may be a role for the
estrogen receptor located on 6q25.1 [79] or GRIK2 (glutamate
receptor, ionotropic, kainate 2) located on 6q16
[80].
6.3.9 t(1;19)(q23;p13)
This aberration is significantly less common in adult
than in pediatric ALL. It was recognized as a separate
entity in adult ALL in only one series where it was found
in 3% of the patients [4]. The genes involved in this
translocation are E2A (early region of adenovirus type
2 encoding helix-loop-helix proteins E12/E47) on chromosome
band 19p13.3 [81, 82] and PBX1 (Pre-B cell leukemia
transcription factor 1) on chromosome band 1q23
[83, 84]. Rare ALL cases with t(1;19)(q23;p13.3) lack E2A/
PBX1 fusion gene [85]. A recent study of a t(1;19)-positive
cell line with pre-B cell phenotype identified a novel
gene fusion between the MEFD2D (myocyte enhancer
factor 2D) gene at 1q22 and DAZAP1 (deleted in azoospermia
associated protein 1) gene at 19p13.3 [86]. It is
currently unknown how frequent the MEF2D/DAZAP1
fusion is among adults with ALL.
At the molecular level, ENA/PBX1 ALL has a unique
gene expression pattern [28]. In addition to the potential
of this pattern to serve for diagnostic purposes,
some of the genes identified can provide insights into
the biology of this disease. For example, gene profiling
of pediatric ENA/PBX1 ALL led to the identification of
high expression levels of the c-MER gene in pretreatment
samples [28]. c-MER is a receptor tyrosine kinase
[87] with known transforming abilities [88]. Targeting
c-MER may be a potential future therapeutic approach
for this disease.
6.3.10 Extrachromosomal Amplification of the
NUP214/ABL Fusion Gene in T-Cell ALL
Two recent studies revealed a novel genetic phenomenon
in T-cell ALL, namely cryptic extrachromosomal
amplification of a segment from chromosome 9 containing
the ABL gene. Barber et al. [89] were the first
to report that amplification involving the ABL gene occurred
in five of 210 (2.3%) children and three of 70
(4.3%) adults with T-cell ALL, even though there was
no cytogenetic evidence of amplification such as double
minutes. The authors suggested that amplified ABL sequences
were located on submicroscopic circular extrachromosomal
DNA molecules called episomes. No amplification
was detected among over 1600 pediatric and
300 adult patients with B-cell ALL screened with the
same probe set [89]. A subsequent study [90] confirmed
the episomal localization of the amplified material, and
extended these observations by demonstrating that amplified
sequences on episomes contained a fusion between
ABL and NUP214 (nucleoporin), a gene also located
at 9q34. Notably, further analyses have revealed
that NUP214/ABL is a constitutively activated tyrosine
kinase activating similar pathways as BCR/ABL and is
sensitive to inhibition with imatinib. While creation
and amplification of NUP214/ABL fusion gene likely
represents a genetic event of primary significance, most
patients had also concurrent rearrangements, that is